An elevated blood plasma level of Factor VIIa is a risk factor for cardiovascular disease and abnormalities of the coagulation system. Uncontrolled FVIIa activation can lead to occlusive arterial thrombosis and thromboembolism which can produce unstable angina, myocardial infarction, and stroke. It is estimated that this year 1.1 million Americans will have a new or secondary heart attack, and about one third of them will die. This makes arterial thrombotic diseases the single leading cause of death in America. Stroke killed an estimated 158,000 people in 1995 and is the third largest cause of death (ranking behind heart disease and all forms of cancer). Stroke is also the single leading cause of disability in the United States.
Thrombosis in the veins deep in thighs or calves (deep vein thrombosis) can lead to ischemia, pain, tenderness, and discoloration of the affected area. A major complication of venous thrombosis is pulmonary embolism, i.e., a clot breaks free and travels through the venous circulation and right heart to the pulmonary circulation, where it blocks an artery of the lung. Pulmonary function is compromised and death may follow. It is estimated that there are about 50,000 deaths per year resulting from pulmonary embolism (Moser, 1990).
FVIIa activation can also result from gram-negative bacteremia which causes half of the cases of lethal septic shock acquired during hospitalization. Bacterial lipopolysaccharide (LPS) and inflammatory mediators mediate some of the sequelae including a coagulopathy that may be triggered by expression of tissue factor (TF) on macrophages and endothelial cells.
Accordingly, antithrombotic agents have been researched and developed for use in treating cardiovascular and other diseases. Presently, antithrombotic agents include heparin, coumarin, and aspirin, among others. There are, however, limitations with these agents. For example, both heparin and coumarin have a highly-variable dose-related response, and their anticoagulant effects must be closely monitored to avoid a risk of serious bleeding. The erratic anticoagulant response of heparin is likely due to its propensity to bind non-specifically to plasma proteins. Aspirin has a limited efficacy and at high doses presents a risk of gastrointestinal bleeding. Thrombin inhibitors and their drawbacks are further discussed in WO 96/20689 to duPont Merck Pharmaceutical Co.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness and bioavailability and/or having fewer side effects. There is particularly an interest in developing agents that can selectively and directly inhibit key factors in the complicated coagulation process. The present invention provides compounds useful as inhibitors of Factor VIIa. Amino-based compounds useful as IMPDH inhibitors are disclosed in U.S. Pat. No. 6,399,773, and compounds useful as IMPDH inhibitors and Factor VIIa inhibitors are disclosed in U.S. patent application Ser. No. 09/997,963, filed Nov. 29, 2001, a continuation-in-part application to U.S. patent application Ser. No. 09/428,432. Additionally, compounds useful in treating Factor VIIa conditions are described in U.S. provisional application Ser. No. 60/389,832, titled “Ureido-Substituted Aniline Compounds Useful As Serine Protease Inhibitors,” filed Jun. 19, 2002, with common inventors herein and assigned to the present assignee. Each of the patents, patent applications, and articles cited herein are incorporated herein by reference.